Calcium mupirocin non-aqueous nasal spray for otitis media or for recurrent acute bacterial sinusitis

ABSTRACT

Mupirocin or a salt or ester thereof may be used to treat recurrent sinusitis and recurrent otitis, in particular with novel spray or cream formulations adapted for administration to the nasopharynx

USE

This is a divisional of application Ser. No. 08/940,730 filed Sep. 30,1997; now U.S. Pat. No. 6,001,870 which claims priority to ForeignApplication Nos. GB9719203.3 filed Sep. 11, 1997 and GB9716805.8 filedAug. 9, 1997; which claims the benefit of U.S. Provisional ApplicationSer. Nos. 60/027,223 filed Oct. 1, 1996; 60/027,222 filed Oct. 1, 1996;and Ser. No. 60/027,224 filed Oct. 1, 1996.

The present invention relates to the use of mupirocin or a salt or esterthereof in treating certain bacterial infections, in particularrecurrent otitis media and recurrent sinusitis, and to formulations foruse in such treatment.

Mupirocin, formerly known as pseudomonic acid, is a therapeuticallyuseful compound which exhibits good antibacterial activity, mainlyagainst Gram-positive bacteria, but also against some Gram-negativebacteria such as Haemophilus influenzae and Moraxella catarrhalis. Itacts as a selective reversible inhibitor of bacterial iso-leucyl t-RNAsynthetase, thereby inhibiting bacterial protein synthesis (see MerckIndex, 11th edn, 1989, 993 and references therein). The compound has anester moiety which is susceptible to metabolism, effectively excludingthe systemic use of the compound. It is however clinically effective asa topical agent.

Topical antibacterial compositions comprising mupirocin are marketed bySmithKline Beecham under the trade names Bactroban Ointment andBactroban Nasal. The first product is an ointment comprising a watersoluble polyethylene glycol base (see also EP 0 095 897-A, BeechamGroup) whilst the second product comprises the calcium salt of mupirocinin a white soft paraffin based ointment containing a glycerin ester (seealso EP 0 167 856-A, Beecham Group). More recently, topical creamscomprising mupirocin or a salt thereof have been described(PCT/US94/12026, SmithKline Beecham). The formulation comprising thecalcium salt of mupirocin in a white soft paraffin based ointmentcontaining a glycerin ester (Bactroban Nasal) is particularly usefulwhen applied to the anterior nares for the prophylactic eradication ofthe nasal carriage of Staph aureus. More recently, it has been foundthat the impact of such application is limited to the anterior nares.There is no significant reduction in the colonisation (by H. influenzae,S. pneumonia and M. catarrhalis) of the nasopharynx (unpublished).

A further potential therapeutic use of mupirocin has been described byNsouli et al (poster presented at the Annual Meeting of the AmericanCollege of Allergy, Asthma and Immunology, Nov. 10--15, 1995 andpublished in Annals of Allergy, Asthma and Immunology, January 1996,76(1), 117). A spray formulation comprising Bactroban Ointment dilutedin a 1:9 ratio with a saline solution (Ocean, Fleming & Co) was shown tobe effective in reducing the incidence of recurrent paranasal sinusitiswhen administered twice daily (two `puffs` of spray, estimated to beabout 150-200μl) over a seven month period. It is believed that efficacyof the mupirocin/saline combination is the result of eradication ofnasal carriage of pathogenic bacteria associated with the recurrentepisodes as the formulation would have no direct access to the sinusmucosa due to a small ostium which separates the nasopharynx from themaxillary sinuses. This dosage regimen may however not be ideal as thereis concern that the use of a relatively low dosage over a prolongedperiod may encourage the development of mupirocin resistant bacteria.Furthermore, there may also be concerns about the desirability of thelong term usage of aqueous solutions of mupirocin, given the knownsusceptibility of mupirocin to degradation in such an environment. Therestill remains the problem of providing a method of treatment forrecurrent sinusitis which is devoid of the concerns mentioned above. Inaddition, there was no suggestion of other diseases which might besusceptible to similar treatment.

Otitis media is a disease state commonly seen in infants and youngchildren. The acute condition is normally successfully treated with asystemic antibacterial agent such as amoxycillin, optionally incombination with potassium clavulanate. H. influenzae, S. pneumonia andM. catarrhalis are generally considered to be the most common bacterialpathogens. There however remains the problem of treating the recurrentpainful episodes.

Accordingly, in a first aspect, the present invention provides for theuse of mupirocin or a pharmaceutically acceptable ester or salt thereofin the manufacture of a medicament for the prophylactic treatment ofbacterial infection associated with colonisation of the nasopharyrx bypathogenic organisms, and in which the medicament is adapted foradministration to, and residence within, the nasopharyrlx; excluding theuse of a 0.2% saline solution of mupirocin for treating recurrentsinusitis, administered at a dosage of less than 1 mg a day, twice dailyon a continuing basis.

Typical bacterial infections include recurrent otitis media andrecurrent sinusitis.

Accordingly, in a further aspect, the present invention provides for theuse of the use of mupirocin or a pharmaceutically acceptable ester orsalt thereof in the manufacture of a medicament for the prophylactictreatment of recurrent otitis media.

In addition, the present invention also provides for the use ofmupirocin or a pharmaceutically acceptable ester or salt thereof in themanufacture of a medicament for the prophylactic treatment of recurrentsinusitis.

As used herein, the term `prophylactic treatment` includes not onlycomplete elimination of the bacterial infection, for instance recurrentotitis media or recurrent sinusitis, but also a partial elimination ofthereof, that is a reduction in the number of acute episodes.

It is believed that the successful treatment of bacterial infections,such as recurrent otitis media and recurrent sinusitis, is associatedwith the elimination or reduction of nasal carriage of pathogenicbacteria such as S. aureus, H. influenzae, S. pneumonia and M.cararrhalis, in particular colonisation of the nasospharynx by suchorganisms.

Accordingly, in a further aspect, the present invention provides for theuse of mupirocin or a pharmaceutically acceptable ester or salt in themanufacture of a medicament for reducing or eliminating the nasalcarriage of pathogenic organisms associated with recurrent otitis media,which medicament is adapted for nasal administration, in particular,focussed delivery to the nasopharynx.

To lessen the risk of encouraging the development of mupirocin resistantorganisms, it is preferred to administer of mupirocin or apharmaceutically acceptable salt or ester thereof on an intermittent,rather than a continual, basis.

Accordingly, in a further aspect, the present invention provides the useof mupirocin or a pharmaceutically acceptable salt or ester thereof(hereinafter referred to as drug substance) in the manufacture of amedicament adapted for administration to the nasopharynx and which isadministered to a patient in need thereof on an intermittent basis.

In a suitable intermittent treatment regimen, drug substance (mupirocinor a pharmaceutically acceptable ester or salt) is administered on adaily basis, for a small number of days, for instance from 2 to 10,suitably 3 to 8, more suitably about 5 days, the administration thenbeing repeated after an interval, for instance, on a monthly basis overa period of months, for instance up to six months.

Less preferably, the drug substance may be administered on a continuing,daily basis, over a prolonged period, for instance several months.

Suitably drug substance is administered twice a day. Suitably, drugsubstance is administered during the winter months when bacterialinfections such as recurrent otitis media and recurrent sinusitis tendto be more prevalent.

Suitably, drug substance is administered at a dosage of from I to 10 mg,preferably from 3 to 8, typically about 5mg, in each nostril, twice aday.

The drug substance is administered to the nasopharynx, in particular theanterior nasopharynx.

Suitable pharmaceutically acceptable salts of mupirocin are well knownin the art and include alkali metal salts such as sodium and lithium andalkaline earth metal salts such as calcium, of which the calcium salt ispreferred, in particular the crystalline dihydrate form thereofdescribed in EP 0 167 856-A (Beecham Group), as well as other metalsalts, for instance silver and aluminum salts and ammonium substitutedammonium salts. The salts may be anhydrous or may be in the form ofpharmaceutically acceptable solvates, for instance alcoholates and,especially, hydrates. Preferred salts include the calcium, silver andlithium salts, in particular the calcium salt. In the case of thecalcium salt of mupirocin, the crystalline salt, preferably thecrystalline hydrated calcium salt, more preferably the crystallinedihydrate salt, is used. Preferably, the crystalline hydrated calciumsalt is used.

Accordingly, in a further aspect, the present invention provides for theuse of the crystalline calcium dihydrate salt of mupirocin in themanufacture of a medicament for the prophylactic treatment of conditionsassociated with bacterial colonisation of the nasopharynx.

Suitable pharmaceutically acceptable esters are well known in the artand include lower alkyl esters, especially the methyl and ethyl esters.

Suitably, the drug substance is present in medicaments for use in thepresent invention inn between 0.01 and 10%, preferably 0.1 and 5%, morepreferably 1 and 5%. Suitable amounts include 2% and 4% by weight of themedicament. It is preferred to avoid low level dosages of drug substanceas this might increase the risk of the development of mupirocinresistant bacteria.

Accordingly, in a further aspect, the present invention provides for theuse of mupirocin or a pharmaceutically acceptable salt or ester thereofin the manufacture of a medicament for the prophylactic treatment ofbacterial infection, characterised in that the medicament isadministered to the nasopharynx and comprises from 0.5 to 5% by weightof mupirocin or a pharmaceutically acceptable salt or ester.

Preferred compositions for administration include those adapted forfocussed delivery to, and residence within, the nasopharynx. The term`focussed delivery` is used to mean that the composition is delivered tothe nasopharynx, rather than remaining within the nares. The term`residence` within the nasopharynx is used to mean that the compositiononce delivered remains within the nasopharynx over a course of severalhours, rather than being washed away more or less immediately. These twoaspects may be conveniently studied by γ (gamma) ray scintigraphy.Suitable such compositions include sprays and creams.

Accordingly, in a further aspect, the present invention provides for asprayable pharmaceutical formulation comprising:

(a) an amphiphilic agent that increases in viscosity on contact withwater;

(b) a non-aqueous diluent for the amphiphilic agent,

(c) powdered drug substance in suspension.

Amphiphilic agents are substances containing both hydrophilic andlipophilic groups. In liquid form, these agents are generally capable ofspontaneous self-association in the presence of water, with a consequentincrease in viscosity. This self-association results in a change inproperties ranging from the formation of viscous liquids to semi-rigidgels. This behaviour has been characterised as due to the formation oflong range order in the liquid system giving several distinct phaseswhich have been called "liquid crystalline phases".

Materials known to exhibit such properties and which are suitable foruse in a pharmaceutical formulation include mono-glycerides such asmono-olein and mono-linolein, phospholipids such as phosphatidylcholines, and galactolipids such as galactoyl-diglycerides.

Typically the monoglycerides are long-chain fatty acid monoglycerides,optionally comprising up to 10% (w/w) of a long-chain fatty aciddiglyceride and/or a small amount by weight of a free long-chain fattyacid. The mono- and di-glycerides may each include blends of differentlong-chain fatty acid mono- and di-glycerides. Suitable long-chain fattyacid monoglycerides include glycerol monooleate, glycerol monopalmitateand glycerol monostearate. Suitable commercially available examples ofsuch include the products available under the trade names MYVEROL, suchas MYVEROL 18-99, MYVATEX, MYVAPLEX, and GMORPHIC 80 respectively, fromEastman Kodak Chemicals, Rochester, N.Y. A further useful long-chainfatty acid monoglyceride- containing product is ARLACEL 186 (availablefrom ICI Americas Inc.) which includes, in addition to glycerolmonooleate, propylene glycol (10%). The main fatty acids of MYVEROL18-99 are oleic acid (61%), linoleic acid (21%), linolenic acid (9%) andpalmitic acid (4%). Suitably in such long-chain monoglycerides, themajor fatty acid component is a C₁₈ -saturated, monounsaturated orpolyunsaturated fatty acid, preferably a C₁₈ -monounsaturated orpolyunsaturated fatty acid. Suitably the monoglyceride will have an HLBvalue in the range of about 2.5 to 6. The HLB value of the productMYVEROL 18-99 is 3.7.

In the present invention the amphiphilic substance is preferablyglyceryl mono-oleate (mono-olein). As indicated above, in itscommercially available form, glyceryl mono-oleate is a material which ispredominantly glyceryl mono-oleate but also contains minor amounts ofrelated mono and di-glycerides. Accordingly, the amount that iseffective in a particular spray formulation will vary dependent on thelevel of glyceryl mono-oleate in the commercial material used.

To obtain a sprayable formulation, the amphiphilic substance is combinedwith a liquid diluent. The diluent is selected on the basis ofcompatibility e.g. producing a stable blend with the amphiphilic agent,and the ability to achieve a sprayable blend without excessive dilutionthat will reduce the self-association on contact with water and detractfrom the desired viscosity increase. Typically, a diluent is apharmaceutically acceptable oil, most preferably a fatty acidtriglyceride, typically vegetable (i.e. plant derived) oil, sincemineral oils such as paraffin oil have been implicated in undesirableside effects when inhaled. Suitable vegetable oils include coconut oil,sesame oil and soya bean oil. In this invention, the preferred diluentis a vegetable oil, most preferably coconut oil, that has beenfractionated so that it is predominantly medium chain lengthtriglycerides. Typically the proportion of amphiphilic agent to oil isfrom 2:1 to 1:4, preferably 1:1 to 1:2. Ideally, the amount of diluentis adjusted so that the formulation is of a viscosity that is suitablefor spray delivery at 20° C. or above.

Suitable medium-chain fatty acid triglycerides for use in the presentinvention may be of natural, semi-synthetic or synthetic origin and mayinclude blends of different medium chain fatty acid triglycerides. Theterm "mediun-chain fatty acid" as used herein refers to a fatty acidhaving from 6 to 12, preferably 8 to 10 carbon atoms which may bebranched or unbranched, preferably unbranched and which may beoptionally substituted. Certain neutral plant oils, such as fractionatedcoconut oils, provide convenient sources of medium-chain fatty acidtriglycerides. The triglyceride suitably comprises from 50 to 100% (w/w)of caprylic (C₈) acid and from 0 to 50% (w/w) of capric (C₁₀) acidtriglycerides. Suitable examples include those available under the tradenames MYRITOL; CAPTEX (Karlshams Lipid Specialties, Columbus Ohio), forinstance CAPTEX 355, CAPTEX 300, CAPTEX 350, CAPTEX 850 and CAPTEX 8000;MIGLYOL (BASF), for instance the grades MIGLYOL 810, MIGLYOL 812 ANDMIGLYOL 818 (which also comprises a linoleic acid triglyceride) andMAZOL 1400 (Mazer Chemical, Guernee, II). The fatty acid content ofrepresentative products is: CAPTEX 355™--CAPROIC ACID (2%), CAPRYLICACID (55%) and capric acid (42%); CAPTEX 8000--at least 98% caprylicacid, MYGOL 810--caproic acid (2%), caprylic acid (65-75%), capric acid(25-35%) and MIGLYOL 812--caproic acid (3%), caprylic acid (50-65%),capric acid (30-45%) and lauric acid (5%) (manufacturer's data).

In the present formulations, the drug substance is used at between 2 and8%, suitably between 3 and 5%, typically about 4%, by weight of theformulation. It is preferred to use a relatively high dosage level, toreduce the risk of the development of bacterial resistance. Also, toavoid excessive delivery volumes which will be uncomfortable in nasaladministration, the drug substance is preferably present at a relativelyhigh loading compared to other topical administration formulations.

Suitably, the drug substance is micronised calcium mupirocin dihydrate.Suitably the drug substance has a particle size less than 100 μm,preferably less than 10 μm.

The sprayable formulations of this invention are especially suitable fordelivery to and residence within the nasopharynx, because in the humidenvironment of the nasal passages they increase in viscosity by contactwith water, and so are better able to resist wash-out when in contactwith nasal surfaces.

Other sprayable formulations for use in the prsent invention includesolutions of drug substance, preferably mupirocin, in aqueouspolyethylene glycol. Such sprays may be conveniently prepared on anextemporaneous basis by diluting a pharmaceutical composition comprisingdrug substance, preferably mupirocin, in polyethylene glycol, or aderivative thereof, with an aqueous solution, for instance water, or,preferably, a saline solution. Suitable such compositions are describedin EP 0 095 897-A2 (Beecham Group). Suitably, the pharmaceuticalcomposition comprises from 0.01 to 50% mupirocin in polyethylene glycol,suitably a mixture of polyethylene glycol 400 and polyethylene glycol4000. In a representative example, the pharmaceutical compositioncomprises 2% mupirocin in mixture of polyethylene glycol 400 (59%) andpolyethylene glycol 4000 (39%). Suitably, the mupirocin containingcomposition is diluted with aqueous solution in a ratio of from 1:1 to1:20, more suitably 1:5 to 1:15, preferably about 1:9 to 1:10. Suitably,in the nasal spray, drug substance is incorporated at between 0.01 and1%, suitably 0.1 to 0.5% by weight of the composition. Suitably suchaqueous compositions comprising mupirocin are stored at about 5° C. andare not stored for prolonged periods, as mupirocin is known to besusceptible to degradation on prolonged exposure to an aqueousenvironment.

The mupirocin formulation and aqueous solution for the extemporaneouspreparation of the nasal spray may be conveniently provided in a kit.Accordingly, in a further aspect, the present invention provides for akit comprising, in a first part, a pharmaceutical formulation comprisingdrug substance, preferably mupirocin, in polyethylene glycol, or aderivative thereof, as hereinbefore described, and, in a second part, anaqueous solution. The first and second parts may be supplied in separatecontainers or in single container with the two parts separated by abarrier which is removed or broken prior to use. Suitably the kitincludes a container adapted for use as a nasal spray device.

Further suitable formulations include creams adapted for focusseddelivery to the nasopharynx. Such formulations with appropriateviscosity characteristics may be provided in containers adapted fornasal administration, for instance having an extended nozzle.

According, in a further aspect, the present invention provides apharmaceutical formulation consisting essentially of

2-8% by wt. of drug substance;

50-70% by wt. of a fatty acid triglyceride;

2-6% by wt. of a polyoxyethylene ether or ester surfactant;

2-4% by wt. of a fatty alcohol or ester;

30-40% by wt. of water; and

up to 2% by wt. of conventional additive such as preservatives andflavourings.

For nasal administration the issue of patient comfort is important incompliance with the intended treatment regime. The formulation of thisinvention provides a low viscosity cream that is easy to administer andwhich readily changes in consistency and softens in the temperatureconditions of the nose. Accordingly when inserted into the upper regionsof the nose it can be transported deeper into the nasal passages bynatural processes. The composition is intended to be in the form of anoil-in-water cream emulsion. In view of the large triglyceride contentwhich provides the desired consistency for nasal administration, and therelatively low content of surfactant, the amounts of the componentswithin the above ranges must be selected for individual components byroutine trials to ensure that an oil-in-water emulsion is obtained.

The fatty acid triglycerides are typically vegetable (i.e.plant-derived) oils, such as coconut oil, sesame oil or soya bean oil.An especially suitable vegetable oil is one that has to beenfractionated so that it is predominantly medium chain lengthtriglycerides.

Suitable medium-chain fatty acid triglycerides for use in the presentinvention may be of natural, semi-synthetic or synthetic origin and mayinclude blends of different medium chain fatty acid triglycerides. Theterm "medium-chain fatty acid" as used herein refers to a fatty acidhaving from 6 to 12, preferably 8 to 10 carbon atoms which may bebranched or unbranched, preferably unbranched and which may beoptionally substituted. Certain neutral plant oils, such as fractionatedcoconut oils, provide convenient sources of medium-chain fatty acidtriglycerides. The triglyceride suitably comprises from 50 to 100% (w/w)of caprylic (C₈) acid and from 0 to 50% (w/w) of capric (C₁₀) acidtriglycerides. Suitable examples include those available under the tradenames MYRITOL; CAPTEX (Karlshams Lipid Specialties, Columbus Ohio), forinstance CAPTEX 355, CAPTEX 300, CAPTEX 350, CAPTEX 850 and CAPTEX 8000;MIGLYOL (BASF), for instance the grades MIGLYOL 810, MIGLYOL 812 ANDMIGLYOL 818 (which also comprises a linoleic acid triglyceride) andMAZOL 1400 (Mazer Chemical, Guemee, II). The fatty acid content ofrepresentative products is: CAPTEX ₃₅₅ ™--CAPROIC ACID (2%), CAPRYLICACID (55%) and capric acid (42%); CAPTEX 8000--at least 98% caprylicacid, MYGOL 810--caproic acid (2%), caprylic acid (65-75%), capric acid(25-35%) and MIGLYOL 812--caproic acid (3%), caprylic acid (50-65%),capric acid (30-45%) and lauric acid (5%) (manufacturer's data).

The polyoxyethylene ether or ester used in this invention is one whichwill function as a non-ionic surfactant. Especially suitable materialsinclude polyoxyethylene glycol monocetyl ethers, such as Cetomacrogol1000. Other suitable non-ionic surfactants include:

(a) polyoxyethylene fatty acid esters, for example polyoxyethylenestearic acid esters of the type available under the trade name MYRJ (ICIAmericas, Inc.), for instance the product MYRJ 52 (a polyoxyethylene 40stearate);

(b) polyoxyetheylene-sorbitan fatty acid esters (polysorbates), forexample the mono- and tri-lauryl, palmityl, stearyl and oleyl esters,for instance the polyoxyethylene sorbitan monooleates available underthe trade name of TWEEN (ICI Americas Inc.), such as TWEEN 20, 21, 40,60, 61, 65, 80, 81 and 85, of which class TWEEN 80 is especiallypreferred;

(c) polyoxyethylene glycol long-chain alkyl ethers, such aspolyoxyethylated glycol lauryl ether; and

(d) polyoxyethylene glycol long-chain alkyl esters, such asPEG-monostearate.

For use herein, the surfactant preferably has an HLB value in the rangeof 13 to 20.

As fatty alcohol or ester there may be used any of such materialsconventionally used in pharmaceutical or veterinary formulations such asstearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, myristyl alcoholand glycerin monostearate. Preferably, cetostearyl alcohol is used, or amixture of stearyl alcohol and cetyl alcohol.

A particularly preferred vehicle formulation comprises fractionatedcoconut oil (typically about 55 to 60, especially about 57, parts byweight); polyoxyethylene glycol monocetyl ether (typically about 2 to 4,especially about 3, parts by weight); cetostearyl alcohol (typicallyabout 2 to 4, especially about 3, parts by weight); with water foremulsification, and also preservatives, and flavourings if desired.

Typical preservatives include benzyl alcohol and phenoxyethanol.

Suitably, the drug substance is the calcium salt of mupirocin, inparticular the calcium dihydrate salt. This is preferably present as afinely divided powder. This may be achieved by milling, and mostsuitably by micronising (fluid energy milling) so that the medicamenthas a particle size less than 100 μm, preferably less than 10 μm.

In the formulation of this invention the drug substance is used atbetween 2 and 8%, suitably between 3 and 5%, typically about 4%, byweight of the formulation. It is preferred to use a relatively highdosage level, to reduce the risk of the development of bacterialresistance. Also, to avoid excessive delivery volumes which will beuncomfortable in nasal administration, the drug substance is preferablypresent at a relatively high loading compared to other topicaladministration formulations.

The formulation may typically be administered into the nasal passages bya pump, such as an air lift pump. This may be adapted for nasaladministration by addition of a modified nozzle.

Formulations of this invention may be produced by conventionalpharmaceutical techniques. Thus, for example, the components of thecarrier may be blended by mixing together at an elevated temperatureuntil an emulsion has formed. The mixture may then be cooled to roomtemperature, and, after the addition of any further optionalingredients, stirred to ensure adequate dispersion. The antibiotic maybe added during hot preparation of the base, or may be added withadditional ingredients after cooling of the base. If necessary thecomposition may be provided in sterile condition.

Optional ingredients that may be added if desired include colourings andflavourings.

The skilled person will readily appreciate that in the novel spray andcream formulations hereinbefore described, mupirocin may be replaced byanother antibiotic agent. The present invention encompasses all suchformulations.

The invention is illustrated by the following Examples.

EXAMPLE 1

Spray Formulation

A carrier for a nasal spray formulation was prepared by forming a blendof 67% w/w fractionated coconut oil (medium chain length)* and 33% w/wof glyceryl mono-oleate **. To this blend was added 0.2% w/w of powderedlemon juice flavour, followed by 4% w/w of micronized calcium Mupirocin.

The resultant formulation has a viscosity which is sprayable at 20° C.or above. When sprayed into the nose of a patient, the liquid coats thenasal passages and contact with moisture inside the nose (from themucous membranes, and the humid environment generally) causes thecarrier to thicken. This prolongs the residence time of the sprayedformulation on the nasal surfaces. A spray volume of about 125 μlcontains approximately 5 mg Mupirocin.

*Commercial product Miglyol, obtainable from Huls

** Commercial product Myverol 18-99, obtainable from Eastman

EXAMPLE 2

Cream

An oil-in-water emulsion cream was prepared from the following:

    ______________________________________                                        Calcium Mupirocin         4%                                                    Fractioned Coconut Oil* 57.3%                                                 Polyoxyethylene glycol monocetyl ether 3%                                     Cetostearyl alcohol 3%                                                        Benzyl Alcohol 1%                                                             Phenoxy ethanol 0.5%                                                          Water 35%                                                                     Lemon juice flavour (powdered) 0.2%                                         ______________________________________                                         *Commercial product Miglyol, obtainable from BASF                        

What is claimed is:
 1. A non-aqueous sprayable formulation suitable fornasal delivery of a medicament comprising:(a) an amphiphilic agentselected from the group consisting of: mono-glycerides; phospholipids;and galactolipids; (b) a non-aqueous diluent for the amphiphilic agentwhich is a pharmaceutically acceptable oil; and (c) calcium mupirocin insuspension.
 2. The formulation as claimed in claim 1, wherein theamphiphilic agent is glyceryl mono-oleate (mono-olein).
 3. Theformulation as claimed in claim 1, wherein the diluent is a fatty acidtriglyceride oil.
 4. The formulation as claimed in claim 3, wherein thefatty acid triglyceride oil is selected from the group consisting of:coconut oil; sesame oil; and soya bean oil.
 5. The formulation asclaimed in claim 3, wherein the fatty acid triglyceride has beenfractionated so that it is predominantly medium chain lengthtriglycerides.
 6. The formulation as claimed in claim 1, wherein theproportion of amphiphilic agent to oil is from 2:1 to 1:4.
 7. Theformulation as claimed in claim 1, wherein mupirocin comprises from 1 to10% by weight of the formulation.
 8. The formulation as claimed in claim1, wherein the calcium mupirocin is the calcium dihydrate salt ofmupirocin.
 9. The formulation as claimed in claim 1, wherein the calciummupirocin comprises between 3 and 5% by weight of the formulation. 10.The formulation as claimed in claim 8, wherein the calcium dihydratesalt is a finely divided powder.
 11. The formulation as claimed in claim8, wherein the calcium dihydrate salt is a finely divided powder with aparticle size of less than 100 μm.
 12. A carrier for a nasal sprayformulation comprising 67% fractionated coconut oil (medium chainlength) and 33% glyceryl mono-oleate by weight of the formulation.
 13. Anasal spray formulation comprising calcium mupirocin in a carriercomprising 67% fractionated coconut oil (medium chain length) and 33%glyceryl mono-oleate by weight of the formulation.
 14. The nasal sprayformulation as claimed in claim 1, wherein the formulation is deliveredto the nasopharynx.
 15. A pump comprising the formulation as claimed inclaim 1,.
 16. The pump as claimed in claim 15, wherein said pump is anair lift pump.
 17. A method of treating recurrent acute bacterialsinusitis in a patient in need thereof comprising administering to saidpatient a pharmaceutically effective amount of the formulation accordingto claim
 1. 18. A method of treating otitis media in a patient in needthereof comprising administering to said patient a pharmaceuticallyeffective amount of the formulation according to claim 1.